Dipeptoid prodrugs and the use thereof   

The present application relates to dipeptide-like prodrug derivatives of 2-amino-6-({[2-(4-chlorophenyl)-1,3-oxazol-4-yl]methyl}sulfanyl)-4-(4-{[2,3-dihydroxypropyl]oxy}phenyl)-pyridine-3,5-dicarbonitrile, processes for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for the manufacture of medicaments for the treatment and/or prophylaxis of diseases, especially of cardiovascular disorders. Prodrugs are derivatives of an active ingredient which undergo in vivo an enzymatic and/or chemical biotransformation in one or more stages before the actual active ingredient is liberated. A prodrug residue is ordinarily used in order to improve the profile of properties of the underlying active ingredient [P. Ettmayer et al., J. Med. Chem. 47, 2393-2404 (2004)]. In order to achieve an optimal profile of effects, it is necessary, in this connection, for the design of the prodrug residue, as well as the desired mechanism of liberation, to conform very accurately with the individual active ingredient, the indication, the site of action, and the administration route. A large number of medicaments are administered as prodrugs which exhibit an improved bioavailability by comparison with the underlying active ingredient, for example achieved by improving the physicochemical profile, specifically the solubility, the active or passive absorption properties or the tissue-specific distribution. An example which may be mentioned from the wide-ranging literature on prodrugs is: H. Bundgaard (Ed.), Design of Prodrugs: Bioreversible derivatives for various functional groups and chemical entities, Elsevier Science Publishers B.V., 1985.

Adenosine, a purine nucleoside, is present in all cells and is released under a large number of physiological and pathophysiological stimuli. Adenosine is produced inside cells on degradation of adenosine 5′-monophosphate (AMP) and S-adenosylhomocysteine as intermediate, but can be released from the cell and then exerts, by binding to specific receptors, effects as hormone-light substance or neurotransmitter. To date, the receptor subtypes A1, A2a, A2b and A3 are known [cf. K. A. Jacobson and Z.-G. Gao, Nat. Rev. Drug Discover. 5, 247-264 (2006)]. The activation of A1 receptors by specific A1 agonists leads in humans to a frequency-dependent lowering of the heart rate, without having an effect on the blood pressure. Selective A1 agonists could therefore be suitable, among other things, for the treatment of angina pectoris and atrial fibrillation.

The activation of A2b receptors by adenosine or specific A2b agonists leads to a lowering of blood pressure via the expansion of vessels. The lowering of blood pressure is accompanied by a reflectory increase in heart rate. The increase in heart rate can be reduced by the activation of A1 receptors by specific A1 agonists.

The combined effect of selective A1/A2b agonists on the vascular system and the heart rate therefore results in a systemic lowering of blood pressure without a relevant increase in heart rate. With a pharmacological profile of this kind, dual A1/A2b agonists could be used to treat, for example, hypertension in humans.

The compound 2-amino-6-({[2-(4-chlorophenyl)-1,3-oxazol-4-yl]methyl}sulfanyl)-4-(4-{[2,3-dihydroxypropyl]oxy}phenyl)pyridine-3,5-dicarbonitrile of the formula (A)

is a potent and selective adenosine A1 receptor agonist with a certain dual, A2b-agonist component to its action (see PCT application WO 2009/015776-A1). The substance is presently undergoing in-depth investigation as a possible new active pharmaceutical ingredient for the prevention and therapy of, in particular, cardiovascular disorders. Of particular significance in this context is the enantiomerically pure form of the compound (A), which on the C* carbon atom of the propane-1,2-diol group possesses an R-configuration.

However, the compound (A) has only a limited solubility in water, physiological media and organic solvents, and an only low bioavailability after oral administration of a suspension of crystalline material. On the one hand, this allows intravenous administration of the active ingredient only in very low dosages; infusion solutions based on physiological saline solutions can be produced only with difficulty with conventional solubilizers. On the other hand formulation in tablet form is difficult.

It was therefore an object of the present invention to identify derivatives or prodrugs of compound (A) which have an improved solubility in the media mentioned and/or an improved bioavailability after oral administration and, at the same time, make it possible to have controlled liberation of the active ingredient (A) in the patient\'s body after administration. In addition, further areas of therapeutic use of this active ingredient could be opened up by an improved possibility of intravenous administration.

A review of prodrug derivatives based on carboxylic esters and possible properties of such compounds is given for example in K. Beaumont et al., Curr. Drug Metab. 4, 461-485 (2003).

The present invention relates to compounds of the general formula (I)

in which RPD is a group of the formula

in which means the point of linkage to the respective O atom, is straight-chain (C2-C4)-alkanediyl, L2 is straight-chain (C1-C3)-alkanediyl, R1 and R3 are identical or different and are independently of one another hydrogen or the side group of a natural α-amino acid or its homologs or isomers, R2 and R4 are independently of one another hydrogen or methyl or R1 and R2 or R3 and R4 are in each case linked to one another and, together with the carbon atom to which they are jointly attached, form a 3- to 6-membered saturated carbocycle, R5 is hydrogen or (C1-C4)-alkyl or R5 is linked to R1 and both, together with the atoms to which they are attached, form a pyrrolidine or piperidine ring, R6 and R7 are identical or different and independently of one another are hydrogen or (C1-C4)-alkyl which may be substituted by hydroxyl, (C1-C4)-alkoxy, amino, mono-(C1-C4)-alkylamino or di-(C1-C4)-alkylamino or R6 and R7 are linked to one another and, together with the nitrogen atom to which they are attached, form a 5- or 6-membered saturated heterocycle which may comprise a further ring heteroatom from the series consisting of N and O, and may be substituted one or two times, identically or differently, by (C1-C4)-alkyl, amino, hydroxyl and/or (C1-C4)-alkoxy, or R6 is linked to R3 and both, together with the atoms to which they are attached, form a pyrrolidine or piperidine ring and R6 is hydrogen or carboxyl, and the salts, solvates and solvates of the salts thereof.

Compounds according to the invention are the compounds of the formula (I) and the salts, solvates and solvates of the salts thereof, the compounds which are encompassed by formula (I) and are of the formulae mentioned hereinafter, and the salts, solvates and solvates of the salts thereof, and the compounds which are encompassed by formula (I) and are mentioned hereinafter as exemplary embodiments, and the salts, solvates and solvates of the salts thereof, insofar as the compounds encompassed by formula (I) and mentioned hereinafter are not already salts, solvates and solvates of the salts.

The compounds according to the invention may, depending on their structure, exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore relates to the enantiomers or diastereomers and respective mixtures thereof. The stereoisomerically pure constituents can be isolated in a known manner from such mixtures of enantiomers and/or diastereomers.

Where the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

Salts preferred for the purposes of the present invention are physiologically acceptable salts of the compounds according to the invention. However, salts which are themselves unsuitable for pharmaceutical applications but can be used for example for isolating or purifying the compounds according to the invention are also encompassed.

Besides monosalts, the present invention also includes where appropriate possible polysalts such as di- or trisalts.

Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, e.g. salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds according to the invention also include salts of usual bases such as, by way of example and preferably, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts, derived from ammonia or organic amines having 1 to 16 C atoms, such as, by way of example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, choline, dicyclohexylamine, dimethylaminoethanol, procain, dibenzylamine, morpholine, N-methylmorpholine, arginine, lysine, ethylenediamine, piperidine and N-methylpiperidine.

Solvates refer for the purposes of the invention to those forms of the compounds according to the invention which form a complex in the solid or liquid state through coordination with solvent molecules. Hydrates are a specific form of solvates in which the coordination takes place with water. Solvates preferred in the context of the present invention are hydrates. In the context of the present invention, the substituents have the following meaning unless otherwise specified:

(C1-C4)-Alkyl is in the context of the invention a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be preferably mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.

(C2-C4)-Alkanediyl, is in the context of the invention a straight-chain, α,ω-divalent alkyl radical having 2 to 4 carbon atoms. Examples which may be preferably mentioned are: ethane-1,2-diyl (1,2-ethylene), propane-1,3-diyl (1,3-propylene), butane-1,4-diyl (1,4-butylene).

(C1-C3)-Alkanediyl is in the context of the invention a straight-chain, α,ω-divalent alkyl radical having 1 to 3 carbon atoms. Examples which may be preferably mentioned are: methanediyl (methylene), ethane-1,2-diyl (1,2-ethylene), propane-1,3-diyl (1,3-propylene).

(C1-C4)-Alkoxy is in the context of the invention a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be preferably mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy.

Mono-(C1-C4)-alkylamino is in the context of the invention an amino group having a straight-chain or branched alkyl substituent which has 1 to 4 carbon atoms. Examples which may be preferably mentioned are: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, tert-butylamino.

Di-(C1-C4)-alkylamino is in the context of the invention an amino group having two, identical or different, straight-chain or branched alkyl substituents which each have 1 to 4 carbon atoms. Examples which may be preferably mentioned are: N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N,N-diisopropylamino, N-n-butyl-N-methylamino, N-tert-butyl-N-methylamino.

A 3- to 6-membered carbocycle is in the context of the invention a monocyclic, saturated cycloalkyl group having 3 to 6 ring carbon atoms. Examples which may be preferably mentioned are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

A 5- or 6-membered heterocycle is in the context of the invention a monocyclic, saturated heterocycloalkyl group having a total of 5 or 6 ring atoms which contains one ring nitrogen atom and optionally a second ring heteroatom from the series consisting of N and O. Examples which may be preferably mentioned are: pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl.

The side group of an α-amino acid in the meaning of R1 and R3 encompasses both the side groups of naturally occurring α-amino acids and the side groups of homologs and isomers of these α-amino acids. The α-amino acid may in this connection have both the L and the D configuration or else be a mixture of the L form and D form. Examples of side groups which may be mentioned are: methyl (alanine), propan-2-yl (valine), propan-1-yl (norvaline), 2-methylpropan-1-yl (leucine), 1-methylpropan-1-yl (isoleucine), butan-1-yl (norleucine), tert-butyl(2-tert-butylglycine), phenyl (2-phenylglycine), benzyl (phenylalanine), p-hydroxybenzyl (tyrosine), indol-3-ylmethyl (tryptophan), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 2-hydroxyethyl (homoserine), 1-hydroxyethyl (threonine), mercaptomethyl (cysteine), methylthiomethyl (S-methylcysteine), 2-mercaptoethyl (homocysteine), 2-methylthioethyl (methionine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), carboxymethyl (aspartic acid), 2-carboxyethyl (glutamic acid), 4-aminobutan-1-yl (lysine), 4-amino-3-hydroxybutan-1-yl(hydroxylysine), 3-aminopropan-1-yl(ornithine), 3-guanidinopropan-1-yl (arginine), 3-ureidopropan-1-yl (citrulline).

Preferred α-amino acid side groups in the meaning of R1 are methyl (alanine), propan-2-yl (valine), 1-methylpropan-1-yl (isoleucine), 2-methylpropan-1-yl (leucine), benzyl (phenylalanine), p-hydroxybenzyl (tyrosine), hydroxymethyl (serine), 1-hydroxyethyl (threonine). The L configuration is preferred in each case. Preferred α-amino acid side groups in the meaning of R3 are methyl (alanine), propan-2-yl (valine), 1-methylpropan-1-yl (isoleucine), 2-methylpropan-1-yl (leucine), benzyl (phenylalanine), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 1-hydroxyethyl (threonine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), carboxymethyl (aspartic acid), 2-carboxyethyl (glutamic acid), 4-aminobutan-1-yl (lysine), 3-aminopropan-1-yl (ornithine), 2-aminoethyl (2,4-diaminobutyric acid), aminomethyl (2,3-diaminopropionic acid), 3-guanidinopropan-1-yl (arginine). The L configuration is preferred in each case.

In the context of the present invention it is the case that, for all radicals which occur two or more times, their meaning is independent of one another. If radicals in the compounds according to the invention are substituted, the radicals, unless specified otherwise, may be substituted one or more times. In this context, substitution by one or by two identical or different substituents is preferred; particularly preferred is substitution by one substituent.

Preference is given, in the context of the present invention, to compounds of the formula (I) in which

RPD is a group of the formula

in which # means the point of linkage to the respective O atom, L1 is ethane-1,2-diyl, L2 is methanediyl or ethane-2-diyl, R1 is hydrogen, methyl, propan-2-yl, 1-methylpropan-1-yl, 2-methylpropan-1-yl, benzyl, p-hydroxybenzyl, hydroxymethyl or 1-hydroxyethyl, R2 is hydrogen, R3 is hydrogen, methyl, propan-2-yl, 1-methylpropan-1-yl, 2-methylpropan-1-yl, benzyl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxyethyl, carbamoylmethyl, 2-carbamoylethyl, carboxymethyl, 2-carboxyethyl, 4-aminobutan-1-yl, 3-aminopropan-1-yl, 2-aminoethyl, aminomethyl or 3-guanidinopropan-1-yl, R4 is hydrogen, R5 is hydrogen or methyl or R5 is linked to R1 and both, together with the atoms to which they are attached, form a pyrrolidine ring, R6 is hydrogen or methyl or R6 is linked to R3 and both, together with the atoms to which they are attached, form a pyrrolidine ring, R7 is hydrogen or methyl and R8 is hydrogen or carboxyl, and the salts, solvates and solvates of the salts thereof.

Particular preference is given in the context of the present invention to compounds of the formula (I) in which

RPD is a group of the formula

in which # is the point of linkage to the respective O atom, L1 is ethane-1,2-diyl, L2 is methanediyl, R1 is hydrogen, methyl, propan-2-yl, 1-methylpropan-1-yl, 2-methylpropan-1-yl, hydroxymethyl or 1-hydroxyethyl, R2 is hydrogen, R3 is hydrogen, methyl, propan-2-yl, 1-methylpropan-1-yl, 2-methylpropan-1-yl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxyethyl, 2-carboxyethyl, 4-aminobutan-1-yl, 3-aminopropan-1-yl or 2-aminoethyl, R4 is hydrogen, R5 is hydrogen, R6 is hydrogen or methyl or R6 is linked to R3 and both, together with the atoms to which they are attached, form a pyrrolidine ring, R7 is hydrogen and R8 is hydrogen, and the salts, solvates and solvates of the salts thereof.

The two prodrug groups RPD in the compounds of the formula (I) may be identical or different within the scope of the meanings indicated above. Preferred compounds of the formula (I) are those with prodrug groups RPD that are identical in each case.

Of particular importance are the compounds of the formulae (I-A) and (I-B)

in which RPD has the meaning indicated above, with an S- or R-configuration on the C* carbon atom of the propane-1,2,3-triyl group, and also the salts, solvates and solvates of the salts thereof.

Preferred in the context of the present invention are the compounds of the formula (I-A) with an S-configuration on the C* carbon atom of the propane-1,2,3-triyl group, and also the salts, solvates and solvates of the salts thereof.

Particularly preferred in the context of the present invention are compounds of the formula (I-A) in which the two prodrug groups RPD are each identical, and also the salts, solvates and solvates of the salts thereof.

Further provided by the invention is a process for preparing the compounds of the formula (I) according to the invention in which the two prodrug groups RPD are each identical, characterized in that the compound (A)

either [A] is esterified in an inert solvent in the presence of a condensing agent initially with two or more equivalents of an amino acid of the formula (II) or (III)

in which L1, R1, R2 and R5 have the meanings indicated above and PG is a temporary amino protective group such as, for example, tert-butoxycarbonyl, to give a compound of the formula (IV) or (V)

in which L1, PG, R1, R2 and R5 have the meanings indicated above, then, after elimination of the protective groups PG, this compound is coupled in an inert solvent in the presence of a condensing agent with two or more equivalents of an amino acid of the formula (VI) or (VII)

in which L2, R3, R4 and R8 have the meanings indicated above and R6a and R7a are identical or different and have the meanings indicated above for R6 and R7, respectively, or are a temporary amino protective group, to give a compound of the formula (VIII), (IX), (X) or (XI)

in which L1, L2, R2, R3, R4, R5, R6a, R7a and R8 each have the meanings indicated above, and subsequently any protective groups present are removed again, or [B] is coupled in an inert solvent in the presence of a condensing agent with two or more equivalents of a carboxylic acid of the formula (XII), (XIII), (XIV) or (XV)

in which L1, L2, R1, R2, R3, R4, R5 and R8 have the meanings indicated above and R6a and R7a are identical or different and have the meanings indicated above for R6 and R7, respectively, or are a temporary amino protective group, to give one of the above-recited compounds (VIII), (IX), (X) or (XI), and subsequently any protective groups present are removed again and the compounds of the formula (I) resulting in each case are converted where appropriate with the appropriate (i) solvents and/or (ii) acids or bases into the solvates, salts and/or solvates of the salts thereof.

The transformation (A)→(I) thus takes place either by sequential coupling of the individual amino acid components which are suitably protected where appropriate (process variant [A]) or by direct acylation with a suitably protected dipeptoid derivative (process variant [B]). The coupling reactions (ester or amide formation) are in this case carried out by known methods of peptide chemistry [cf., for example, M. Bodanszky, Principles of Peptide Synthesis, Springer-Verlag, Berlin, 1993; H.-D. Jakubke and H. Jeschkeit, Aminosäuren, Peptide, Proteine, Verlag Chemie, Weinheim, 1982].

Examples of inert solvents for the coupling reactions are ethers such as diethyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, pyridine, dimethyl sulfoxide, dimethylformamide, N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP) or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Dichloromethane, dimethylformamide or mixtures of these two solvents are preferred.

Examples of suitable condensing agents in these coupling reactions are carbodiimides such as N,N′-diethyl-, N,N-dipropyl-, N,N-diisopropyl-, N,N′-dicyclohexylcarbodiimide (DCC) or N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as N,N-carbonyldiimidazole (CDI), 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or isobutyl chloroformate, propanephosphonic anhydride, diethyl cyanophosphonate, bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) or O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TCTU), where appropriate in combination with further auxiliaries such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and as bases are alkali metal carbonates, e.g. sodium or potassium carbonate, or organic amine bases such as triethylamine, N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine or 4-N,N-dimethylaminopyridine. N-(3-Dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) in combination with 4-N,N-dimethylaminopyridine is preferably employed for ester deformation. N-(3-Dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) in combination with 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu) and, where appropriate, a base such as N,N-diisopropylethylamine is preferably used for the amide formation.

The couplings are generally carried out in a temperature range from 0° C. to +60° C., preferably at +10° C. to +30° C. The reactions can take place under normal, under elevated or under reduced pressure (e.g. from 0.5 to 5 bar). They are generally carried out under atmospheric pressure.

The compounds of the formula (I) may also result directly in the form of their salts in the preparation by the processes described above. These salts can be converted where appropriate by treatment with a base or acid in an inert solvent, by chromatographic methods or by ion exchange resins, into the respective free bases or acids. Further salts of the compounds according to the invention can also be prepared where appropriate by exchange of counterions by means of ion exchange chromatography, for example with Amberlite® resins.